1. Field of the Invention
This invention relates to small-molecule inhibitors of interleukin-2.
2. Description of Related Art
The cytokine interleukin-2 is a principal regulator of the Th1, or cell-mediated, immune response [Waldmann et al., xe2x80x9cContrasting Roles of IL-2 and IL-15 in the Life and Death of Lymphocytes: Implications for Immunotherapyxe2x80x9d, Immunity, 2001, 14, 105-110]. When the body launches a Th1 response against its own cells, autoimmune diseases (such as rheumatoid arthritis, multiple sclerosis, uveitis, and psoriasis) occur. Similarly, cell-mediated immunity causes rejection of transplanted organs (allograft rejection) and graft-versus-host disease (GVHD), a serious complication that can occur after bone-marrow transplantation.
The IL-2 receptor system (IL-2R) contains three subunits. The dimeric receptor, containing the beta and gamma subunits, is found on most immune cells; IL-2-mediated signaling through this receptor stimulates basal cell growth of T-cells, natural killer cells, and macrophages. During a Th1 immune response, the alpha chain of the IL-2 receptor (IL-2Rxcex1) is expressed on the surface of activated T-cells. Binding of IL-2 to this trimeric receptor causes the activated T-cells to proliferate, and this T-cell proliferation is in turn responsible for stimulating the cell-mediated immune response.
Currently used immunosuppressive protocols designed to inhibit allograft rejection and GVHD involve the use of general immunosuppressants such as azathioprine, cyclosporin, rapamycin, tacrolimus, mycophenolate mofetil, and corticosteroids, generally in combinations of two or more of these drugs. All of these can cause toxic side effects to non-lymphoid tissues. It would be desirable to develop inhibitors of the Th1 immune response that selectively block the proliferative activity of IL-2/IL-2Rxcex1 binding without affecting the role of IL-2 role in basal cell growth, as these selective IL-2Rxcex1 antagonists should be safer than general inmnunosuppressants.
Recently, two antibodies directed against IL-2Rxcex1 (basiliximab and daclizumab) have been approved for allograft rejection. Studies have shown that these antibodies provide benefits over the standard three-drug (azathioprione, cyclosporin and mycophenolate mofetil or steroids) regime without some of the side effects of that therapy (Berard et al., xe2x80x9cA review of interleukin-2 receptor antagonists in solid organ transplantationxe2x80x9d, Pharmacotherapy 1999, 19, 1127-1137; Nashan, xe2x80x9cThe interleukin-2 inhibitors and their role in low-toxicity regimensxe2x80x9d, Transplantation Proc. 1999, 31 (Suppl. 8A), 23S-26S). However, these antibodies are not orally bioavailable.
Application of new immunosuppressants to autoimmune disease has lagged behind treatments for graft rejection. While autoimmune diseases have diverse manifestations, the up-regulation of the immune response appears to be a common underlying pathology. Important unmet medical needs exist for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS), uveitis, and psoriasis. Several of the therapeutics currently used to treat autoimmune diseases require intravenous, intramuscular or subcutaneous injection, and are thus suboptimal for chronic use. Nevertheless, several ongoing clinical trials are investigating the use of anti-IL-2Rxcex1 antibodies for multiple sclerosis and other autoimmune diseases. See, for example, Brok et al., xe2x80x9cProphylactic and therapeutic effects of a humanized monoclonal antibody against the IL-2 receptor (daclizumab) on collagen-induced arthritis (CIA) in rhesus monkeysxe2x80x9d, Clin. Exp. Immunol. 2001, 124, 134-141.
Thus, despite improved therapies for immunosuppression, autoimmune diseases continue to be important pathologies in need of safe and efficacious treatments. To date, no small-molecule IL-2 antagonists have been reported. It would be desirable to develop a small-molecule orally available inhibitor of the IL-2/IL-2Rxcex1 interaction.
The disclosures of all documents referred to throughout this application are incorporated herein by reference.
In a first aspect, this invention is compounds of formula I or formula Ixe2x80x2 
where,
m is an integer selected from 0, 1, and 2;
n and o are integers independently selected from 0 and 1;
A is selected from the group consisting of N and CH;
B is selected from the group consisting of xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94CH2xe2x80x94, xe2x80x94S(xe2x95x90O)2CH2xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94S(xe2x95x90O)2xe2x80x94, and xe2x80x94S(xe2x95x90O)2xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94;
J is absent or selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CHR15xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CHR15xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CHR15xe2x80x94, xe2x80x94NHxe2x80x94CHR15xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR15xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CHR15xe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH(C1-C6alkyl)-, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH(C3-C12cycloalkyl)-, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94NH2xe2x80x94, xe2x80x94CH2xe2x80x94NH2xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2xe2x80x94NH2xe2x80x94C(xe2x95x90O)xe2x80x94C1-C6alkyl-, xe2x80x94CH2xe2x80x94NH2xe2x80x94C(xe2x95x90O)xe2x80x94CH(C3-C12cycloalkyl)-, and xe2x80x94C(xe2x95x90O)xe2x80x94CHR15xe2x80x94NHxe2x80x94; or
Bxe2x80x94J is selected from the group consisting of xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH(C1-C6alkyl, xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH(C3-C12cycloalkyl)-, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94(C2-C6alkyl), xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94(C2-C6alkyl)-, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CHxe2x80x94 and xe2x80x94S(xe2x95x90O)xe2x80x94CH2xe2x80x94,
L is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94S(xe2x95x90O)2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, CHxe2x95x90CHxe2x80x94CH2xe2x80x94, and xe2x80x94CHxe2x95x90CHxe2x80x94;
M is selected from the group consisting of R9 and an optionally substituted group selected from phenyl, naphthyl, C3-C7-cycloalkyl, and heterocyclyl, the heterocyclyl group being aliphatic, partially unsaturated, or aromatic, and containing 1 or 2 rings each containing 5-7 ring atoms of which 0-3 are hetero atoms selected from N, O and S, provided that at least one ring contains a heteroatom and where any ring carbon or sulfur may optionally be oxidized, the optional substituents being up to three groups selected from R1, R2 and R9; or
M is selected from the group consisting of 
Q is selected from the group consisting of xe2x80x94C(xe2x95x90O)OR16, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CF3, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94S(xe2x95x90O)2xe2x80x94R2, xe2x80x94C(xe2x95x90O)xe2x80x94NR1xe2x80x94OH, 5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl, and tetrazolyl;
X is A when n is 1, and is CH, N, O or S when n is 0;
R1 is selected from the group consisting of hydrogen, (C1-C6)alkyl, halo-(C1-C6)alkyl, and (C3-C6)cycloalkyl;
R2, R3 and R5 are individually selected from the group consisting of hydrogen, cyano, nitro, phenyl, phenoxy, benzyl, C1-C6alkyl, halo, halo-C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, hydroxy, C1-C2alkoxy-methoxy, hydroxy-C1-C6alkyl, formyl, C1-C6alkylcarbonyl, amino, C1-C6alkylamino, aminocarbonyl, C1-C6alkylaminocarbonyl, formylamino, and C1-C6alkylcarbonylamino, where any alkyl or phenyl may optionally be substituted with halo or Q;
R4 selected from the group consisting of R2 and 
xe2x80x83where Ar is a homo- or hetero-aryl group having 1 or 2 rings, each ring containing 5, 6 or 7 ring atoms of which 1-3 may be heteroatoms selected from N, O and S;
R6 is selected from the group consisting of hydrogen, C1-C6alkyl, halo, halo-C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, hydroxy, hydroxy-C1-C6alkyl, HC(xe2x95x90O)xe2x80x94C1-C6alkyl, carboxy, carboxy-C1-C6alkyl, carbonylamino-C1-C6alkyl, aminocarbonyl, (C1-C6alkyl)aminocarbonyl, di(C1-C6alkyl)aminocarbonyl, and aminocarbonyl-C1-C6alkyl;
R7 is selected from the group consisting of hydrogen, C1-C6 alkyl, halo, halo-C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, hydroxy, hydroxy-C1-C6alkyl, HC(xe2x95x90O)-C1-C6alkyl, carboxy, carboxy-C1-C6alkyl, carbonylamino-C1-C6alkyl, aminocarbonyl, (C1-C6alkyl)aminocarbonyl, di(C1-C6alkyl)aminocarbonyl, and aminocarbonyl-C1-C6alkyl;
R7xe2x80x2 is hydrogen; or
R7 R7xe2x80x2 together with the carbon to which they are bonded form xe2x80x94C(xe2x95x90O)xe2x80x94;
R8 is selected from the group consisting of hydrogen, hydroxy, C1-C6alkoxy, C1-C6alkyl, halo, halo-C1-C6alkyl, and C3-C6cycloalkyl;
R9 is selected from the group consisting of xe2x80x94NR10R11, xe2x80x94C(xe2x95x90NR12)xe2x80x94NHR13, xe2x80x94Nxe2x95x90CR14xe2x80x94NR10R11, xe2x80x94NR13xe2x80x94CR14xe2x95x90NR12, and xe2x80x94NR13xe2x80x94C(NR12)xe2x80x94NHR13;
R10, R11, R12, R13 and R14 are independently selected from the group consisting of hydrogen, hydroxy, hydroxy-C1-C6alkyl, C1-C6alkyl, halo-C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, and C3-C7 cycloalkyl; or any member of the group R10, R11, R12, and R13 together with the nitrogen to which it is attached forms a 5, 6 or 7 member heterocycle with any other member of the group, the heterocycle optionally containing one additional heteroatom selected from N, O and S;
R15 is selected from the group consisting of hydrogen, C1-C12alkyl, C3-C7cycloalkyl, aminocarbonyl, C1-C6alkylaminocarbonyl, and di(C1-C6alkyl)aminocarbonyl; and
R16 is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C13cycloalkyl, C6-C10aryl, acetylamino-C1-C12alkyl, C1-C6alkylcarbonyloxy-C1-C6alkyl, and C6-C6aryl-C6-C10aryl-C0-C6alkylcarbonyloxy-C1-C6alkyl, and the pharmaceutically acceptable salts thereof;
provided that the compound is not N-[2-[1-(aminoiminomethyl)-3-piperidinyl]-1-oxoethyl]-4-phenylethynyl-phenylalanine methyl ester or a pharmaceutically acceptable salt thereof.
In a second aspect, this invention is pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of at least one compound of the first aspect of this invention. These compositions find use for the treatment of autoimmune diseases (e.g. rheumatoid arthritis, multiple sclerosis, uveitis, and psoriasis), allograft rejection, and GVHD.
In a third aspect, this invention is a method of treating an animal having disease for which antagonism of IL-2/IL-2R binding is indicated (an interleukin-2 mediated disease), such as autoimmune diseases, allograft rejection, and GVHD, comprising administration to that animal of a therapeutically effective amount of at least one compound of the first aspect of this invention, optionally in conjunction with at least one other conventional therapeutic agent for the disease being treated.
In a fourth aspect, this invention is the use of compounds of the first aspect of this invention in the preparation of medicaments for the treatment of diseases capable of treatment by an antagonist of IL-2/IL-2R binding, such as autoimmune diseases, allograft rejection, and GVHD.
In a fifth aspect, this invention is methods of preparing the compounds of the first aspect of this invention.
Definitions
xe2x80x9cAlkylxe2x80x9d means a linear hydrocarbyl group having the range of carbon atoms specified, or a branched or cyclic hydrocarbyl group having at least 3 carbon atoms within the range of carbon atoms specified. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, cyclopropylmethyl, and hexyl.
xe2x80x9cAnimalxe2x80x9d includes humans and non-human mammals, such as companion animals (cats, dogs, and the like) and farm animals (cattle, horses, sheep, goats, swine, and the like).
xe2x80x9cDiseasexe2x80x9d includes any unhealthy condition of an animal, including injury, particularly interleukin-2 mediated diseases, such as autoimmune diseases (e.g. rheumatoid arthritis, multiple sclerosis, uveitis, and psoriasis), allograft rejection, and graft-versus-host disease.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, or bromo.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with from 1 to 3 halogen atoms selected from fluorine, chlorine, or bromine.
xe2x80x9cPharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d means salts that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts that may be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, e.g. sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Such salts also include acid addition salts formed with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g. acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid). When there are two acidic groups present, a pharmaceutically acceptable salt may be a mono-acid-mono-salt or a di-salt; and similarly where there are more than two acidic groups present, some or all of such groups can be salified.
A xe2x80x9cprotecting groupxe2x80x9d has the meaning conventionally associated with it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for that disease.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).
The compounds of formula Ixe2x80x2 possess a chiral center in the alanine portion of the molecule, where they have the normal (S) configuration. The compounds of this invention may also possess one or more (additional) chiral centers. Methods for the determination of stereochemistry and the separation of stereoisomers are well known to a person of ordinary skill in the art [see the discussion in Chapter 4 of March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., 1992, John Wiley and Sons, New York, N.Y.].
Implicit hydrogen atoms on carbon and sometimes on nitrogen atoms are generally omitted from the formulae for clarity, but should be understood to be present.
Presently Preferred Compounds
While the broadest definition of the invention is set out in the Summary of the Invention, certain compounds of this invention are presently preferred.
Presently preferred compounds of this invention are compounds of formula I that are compounds of formula II 
where the substituents are as defined for formula I;
and the pharmaceutically acceptable salts thereof.
More preferred compounds are compounds of formula II that are compounds of formula III or formula IIIxe2x80x2
where the substituents are as defined for formula I;
and the pharmaceutically acceptable salts thereof.
Other preferred compounds are compounds of formula I that are compounds of formula IV 
a where the substituents are as defined for formula I;
and the pharmaceutically acceptable salts thereof.
Presently preferred classes of compounds of this invention include those where:
(1) R1 is hydrogen or (C1-C6alkyl), especially methyl;
(2) R2 and R3 are hydrogen, C1-C6alkyl, cyano, or halo (especially chloro), and more preferably one or both are chloro;
(3) R4 is 
xe2x80x83especially where one or more of the following preferences applies: Ar is selected form the group consisting of phenyl, furyl, thienyl, oxazolyl, thiazolyl, and pyrrolyl; R5 is hydroxy, C1-C2alkoxy-methoxy or C1-C3-alkoxy; Q is a negatively charged species such as carboxy (or a prodrug thereof) or tetrazolyl; and L is xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94;
(4) B is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94;
(5) J is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94C1-C6alkyl- and xe2x80x94CH2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH(C3-C12cycloalkyl)-;
(6) Bxe2x80x94J combinations are xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH(C1-C6alkyl)-, xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH(C3-C12cycloalkyl)-, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94(C2-C6alkyl)-, xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94(C2-C6alkyl)-, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94 and xe2x80x94S(xe2x95x90O)2xe2x80x94CH2xe2x80x94;
(7) M is selected from the group consisting of R9, 
xe2x80x83especially where M is not R9.
A number of different preferences have been given above, and following any one of these preferences results in a compound of this invention that is more presently preferred than a compound in which that particular preference is not followed (e.g. compounds of formula III or formula IIIxe2x80x2 are more preferred than compounds of formula II that are not compounds of formula III or formula IIIxe2x80x2; and compounds of formula II are more preferred than compounds of formula I that are not compounds of formula II). However, substituent preferences in particular are generally independent [although the Bxe2x80x94J preferences are not entirely independent of the B preferences and J preferences], and additive; and following more than one of these preferences may result in a more presently preferred compound than one in which fewer of the preferences are followed.
Presently particularly preferred compounds of this invention are the compounds of Examples 1 to 76, and the pharmaceutically acceptable salts thereof.
Pharmacology and Utility
The compounds of this invention are antagonists of IL-2/IL-2R binding. Their activity as antagonists of IL-2/IL-2R binding in vitro can be measured by methods such as the scintillation proximity assay described in Example 77 to demonstrate that the compounds inhibit binding of IL-2 to IL-2Rxcex1 in a dose-dependent fashion. Other methods, such as ELISA, enzyme-linked protein binding assays, and energy transfer assays, can also be used.
In addition to these assays demonstrating that compounds antagonize binding of IL-2 to IL-2Rxcex1, other measurements can be used to demonstrate directly the binding of compounds to IL-2. Such methods include NMR, x-ray crystallography, analytical ultracentrifugation, surface plasmon resonance (SPR, Biacore), and isothermal calorimetry. By these methods, compounds of this invention can be shown to bind to IL-2 with one-to-one stoichiometry; furthermore, compounds can be shown to bind at the IL-2 surface that is used to bind IL-2Rxcex1.
Cell-based assays to study inhibition of IL-2/IL-2Rxcex1 binding use phosphorylation of STAT5 as a marker of IL-2 activity on CTLL-2 cells. When IL-2 binds to its receptor, an intracellular signal is transduced from Jak1 and Jak3 proteins to STAT5. Phosphorylated STAT5 then translocates to the nucleus and activates transcription. Inhibition of STAT5 phosphorylation therefore indicates that the compounds interfere with IL-2 mediated signal transduction. For selectivity studies, one can monitor STAT5 phosphorylation in response to IL-15 binding. IL-15 is homologous to IL-2 and signals through the IL-2 dimeric receptor. IL-15 does not bind to IL-2Rxcex1, and selective IL-2 inhibitors should not inhibit IL-15 signaling. A description of the assay is given in Example 78.
The activity of compounds of this invention can be measured in vivo by activity against animal models of the selected disease.
The therapeutic ratio of a compound can be determined for a selected disease, for example, by comparing the dose that gives effective activity in a suitable in vivo model in a suitable animal species, with the dose that gives significant weight loss (or other observable side-effects) in the test animal species.
Pharmaceutical Compositions and Administration
In general, compounds of this invention will be administered in therapeutically effective amounts by any of the usual modes known in the art, either singly or in combination with at least one other compound of this invention and/or at least one other conventional therapeutic agent for the disease being treated. A therapeutically effective amount may vary widely depending on the disease, its severity, the age and relative health of the animal being treated, the potency of the compound(s), and other factors. A representative dose will range from 0.001 to 100 milligrams per kilogram body weight of the animal per day(mg/Kg/day); for example, from 0.01 to 10 mg/Kg/day. A person of ordinary skill in the art will be able without undue experimentation, having regard to that skill and this disclosure, to determine a therapeutically effective amount of a compound of this invention for a given disease.
In general, compounds of this invention will be administered as pharmaceutical compositions by one of the following routes: oral, topical, systemic (e.g. transdermal, intranasal, or by suppository), or parenteral (e.g. intramuscular, subcutaneous, or intravenous injection). Compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions; and comprise at least one compound of this invention in combination with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to persons of ordinary skill in the art, and they, and the methods of formulating the compositions, may be found in such standard references as Gennaro, ed., xe2x80x9cRemington: The Science and Practice of Pharmacyxe2x80x9d, 20th ed., 2000, Lippincott, Williams and Wilkins, Philadelphia, Pa. Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous dextrose solution, and glycols.
The amount of a compound of this invention in the composition may vary widely depending on the type of composition, size of a unit dosage, kind of excipients, and other factors well known to those of ordinary skill in the art. In general, the final composition may comprise from 0.001 percent by weight (% w) to 90% w of the compound of this invention, preferably 0.01% w to 10% w, with the remainder being the excipient or excipients.
A pharmaceutical composition of this invention may optionally contain, in addition to a compound of this invention, at least one other compound of this invention, and/or at least one pharmaceutically active compound selected from compounds conventionally used in the treatment of the selected disease. For example, in the case of allograft rejection, the composition may contain one or more of the conventional immunosuppressants mentioned in the BACKGROUND TO THE INVENTION.
Additionally, compounds conventionally used in the treatment of the selected disease may also be co-administered with compound(s) of this invention. xe2x80x9cCo-administeredxe2x80x9d here includes administration during the course of treatment with the compound(s) of this invention, and is not limited to administration at the same time as the administration of the compound(s) of this invention, depending on appropriate dosing schedules for the conventional compounds and for the compound(s) of this invention.
Preparation of the Compounds of This Invention
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser, xe2x80x9cReagents for Organic Synthesisxe2x80x9d, vols 1-17, 1991, John Wiley and Sons, New York, N.Y.; Rodd, xe2x80x9cChemistry of Carbon Compoundsxe2x80x9d, vols. 1-5 and supps, 1989, Elsevier Science Publishers; xe2x80x9cOrganic Reactionsxe2x80x9d, vols 1-40, 1991, John Wiley and Sons, New York, N.Y.; March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., 1992, John Wiley and Sons, New York, N.Y.; and Larock, xe2x80x9cComprehensive Organic Transformationsxe2x80x9d, 1989, VCH Publishers. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to a person of ordinary skill in the art having regard to this disclosure.
The starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range between about 0xc2x0 C. and 125xc2x0 C.
The preparation of the core of the compounds of formula I may be accomplished by methods similar to those seen in Examples 16 and other like examples; i.e. as in Scheme I below, where substituents and variations in ring size of the compound of formula I have been omitted for clarity. 
As seen in Scheme I, above, a piperidine or piperazine carboxylic acid is protected at the nitrogen, then reacted with dimethylhydroxylamine, followed by reduction with an agent such as lithium aluminum hydride to form the corresponding aldehyde, then treated with a reagent such as dimethyl 1-diazo-2-oxopropylphosphonate to convert the aldehyde into an acetylene. Reaction of the acetylene with an aryl chloride gives an arylacetylene, and this is reacted with an alkylhydrazine to form the imidazole center ring. The resulting compound can be deprotected in the conventional manner.
Elaboration of the aryl group can be accomplished by a variety of methods shown in Scheme II: 
The phenols 98 and 179 can be used to prepare biaryl ether type analogues 180 using, for example, Ullman type couplings as described by, for example, Evans et al., Tetrahedron Lett. 1998, 39, 2937-2940, J. Am. Chem. Soc. 1997, 119, 3395-3396, J. Am. Chem. Soc. 1997, 119, 10539-10540, and Tetrahedron Lett. 1998, 39, 2933-2936). Compounds 98 and 179 may also be used to make the corresponding trifluoromethanesulfonyloxy intermediate 181, using, for example, N-phenyltrifluoromethansulfonimide in the presence of a base such as triethylamine. The triflated phenol 181 is a valuable precursor since it may be used in various palladium-catalyzed transformations to provide further intermediates/analogues such as the carboxylic acid 182 (via palladium-catalyzed carbonylation using carbon monoxide, see, for example, Tetrahedron Lett. 1992, 33, 3939-3942), biaryls, arylvinyls, and arylalkyls 183 and 184 (via Suzuki/Stille/Heck couplings). Compound 181 may also be used to prepare aryl sulfides such as 185 and 186 (see, for example, Nan Zheng et al., J. Org. Chem. 1998, 63, 9606-9607.). Further, triflated phenols such as 181 can be used as substrates for the preparation of substituted aromatic amines such as 187 using conditions developed by, for example, Buchwald (see, for example, J. Org. Chem. 2000, 65, 1158-1174, and references therein). In addition, triflate 181 may be converted to the corresponding aldehyde, 188, using palladium catalysis under a carbon monoxide atmosphere in the presence of a reducing agent such as a trialkylsilane.
Carboxylic acid 182 can be used to make amides such as 189 and esters such as 190. In addition, compound 182 can be subjected to a Curtius rearrangement to provide the aniline 191 which in turn may be converted to amides, ureas, and carbamates 192.
The aromatic aldehyde 188 can be reduced to the corresponding benzylic alcohol 193 or subjected to reductive amination to furnish benzylic amines such as 194. The alcohol 193 may be alkylated or converted to esters to yield compounds such as 195. It may also be converted to an alkylating agent such 196 (for example, a benzylic bromide) which in turn can be used to provide benzylic thiols such as 197.
Elaboration of the xe2x80x94Bxe2x80x94Jxe2x80x94M portion of the molecule may be accomplished by the methods generally described in Examples 1 through 76, and as illustrated in Scheme II 
Referring to Scheme III above, the piperidine derivative 198 (e.g. 25) can be reacted with acylating agents containing a leaving group (e.g., bromine) at, for example, the xcfx89-position to provide alkylating agents such as 199. These alkylating agents may be reacted further with nucleophiles, such as amines or alcohols, to provide compounds (200) with a linkage to a guanidine-like fragment or a guanidine mimetic. Compound 198 may also be acylated to provide xcex1-diketo derivatives such as 201. These compounds may be used in reductive aminations to provide additional linked guanidine type compounds 202. Alternatively, 198 can be acylated to provide acrylic derivatives such as 203, which can be used in a cross-metathesis transformation (for a review and leading references, see: Tetrahedron1998, 39, 2805), yielding compounds 204 which may be further manipulated (reduced) to analogues such as 205.
The preparation of compounds of formula Ixe2x80x2
is accomplished generally by the method of Tilley et al., J. Am. Chem. Soc. 1997, 119, 7589-7590 and its supplemental materials, and Tilley et al., J. Org. Chem. 1995, 55, 906-910, i.e.; 
An optionally ring-substituted tyrosine is protected at the amine nitrogen, then treated with phenyltriflimide to give the 4-trifluoromethanesulfonyloxy compound. This is reacted with an optionally ring-substituted phenylacetylene in the presence of a palladium catalyst, and the amine deprotected with acid. Elaboration of the amine to form the compounds of formula Ixe2x80x2 proceeds in the same manner as for the compounds of formula I. It is assumed in this scheme that R16 is not hydrogen or acetylamino-C1-C12alkyl; if R16 is desired to be either of these, then the scheme may be carried through using as R16 a protecting group which is removed by hydrolysis at the appropriate point in the synthesis to give the compound of formula Ixe2x80x2 where R16 is hydrogen, and optionally then treated to give the appropriate N-alkylcarbamate.
The syntheses are illustrated generally in the following Examples 1-76.
Other methods of synthesis are also usable, and a person of ordinary skill in the art, having regard to that skill, this disclosure, and the references cited herein, will be able to prepare desired compounds of this invention without undue experimentation.